Abstract

Background: Vascular endothelial cells (ECs) play an important role in angiogenesis and inflammatory responses. MCPIP (also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells. To directly test the role of endothelium-derived MCPIP in cardiovascular pathophysiology, we specifically targeted deletion of the murine MCPIP gene in the endothelium by using the loxP/Cre system.
Methods and Results: A floxed MCPIP knock in mouse line was crossbred with an endothelial-specific VEcadherin5-Cre driver mouse line to generate offspring with deletion of the MCPIP gene in ECs (ECKO). Ablation of MCPIP in ECs resulted in systemic inflammation, anemia, splenomegaly, increased vessel permeability, muscle wasting, endothelial dysfunction, thrombus formation, impaired blood perfusion, and reduced lifespan in these mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in the ECKO mice, suggesting a hypercytokinemia. These mice also were more susceptible to lipopolysaccharide-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia and stroke models, as well as in wound healing. This effect was associated with an increased cellular infiltration, cytokine expression, and decreased angiogenic factors. Moreover, MCPIP-deficient ECs displayed decreased vascular sprouting and tube elongation in ex vivo aortic ring assay. MCPIP-knockdown in cultured ECs enhanced NF-κB activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction.
Conclusions: These data show, for the first time, that constitutive expression of MCPIP in ECs is essential to maintain ECs in a quiescent state by serving as an important negative feedback regulator that keeps the inflammatory signaling suppressed. This provides a novel mechanism for maintaining endothelial homeostasis and function.